Project Summary More than one million civilians experience a coma from severe traumatic brain injury (TBI) each year, and thousands of military personnel have experienced a traumatic coma since the start of Operation Enduring Freedom in 2001. However, there are currently no treatments to promote early recovery of consciousness in the intensive care unit (ICU). Without knowing whether a patient can recover consciousness, many families withdraw life-sustaining therapy, a grave decision that accounts for up to 70% of TBI deaths in the ICU. Our multidisciplinary team of investigators with expertise in TBI, critical care, disorders of consciousness (DoC), neuroimaging, electrophysiology, ethics, statistics, pharmacology, and clinical trials will establish the Connectome-Based Clinical Trial Platform (CCTP), a new mechanistic paradigm for developing targeted therapies that promote early recovery of consciousness in the ICU. The CCTP is based upon two fundamental innovations: 1) predictive biomarkers to identify patients for clinical trials based on specific ascending arousal network (AAN) connectome phenotypes that can be targeted by new therapies; and 2) pharmacodynamic biomarkers to measure how targeted therapies modulate the AAN, reactivate the cerebral cortex, and restore consciousness. In addition to establishing the CCTP, we will test the feasibility and utility of the CCTP in Phases 1 and 2a of an inaugural clinical trial called STIMPACT: Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness. The central hypothesis of the STIMPACT trial is that preservation of dopaminergic ventral tegmental area (VTA) connections within the AAN connectome predicts a patient?s response to intravenous methylphenidate (IV MPH), a dopamine reuptake inhibitor that potentiates dopamine neurotransmission by VTA neurons. In this New Innovator Award, we will develop MRI- and EEG-based biomarkers for STIMPACT, including a VTA structural connectome biomarker to predict patients? responses to IV MPH, and VTA functional connectome biomarkers to measure responses to IV MPH. In Phase 1 of STIMPACT, we will test the safety, pharmacokinetics and pharmacodynamics of IV MPH in patients with severe TBI and DoC in the ICU. In Phase 2a of STIMPACT, we will test the hypothesis that the VTA structural connectome biomarker predicts pharmacodynamic responses to IV MPH in a single-center, double-blinded, randomized, placebo-controlled, cross-over design trial. By promoting early recovery of consciousness in the ICU, the CCTP will reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate self- expression, enable autonomous decision-making, decrease ICU complications related to immobility, and increase access to post-ICU rehabilitative care. The CCTP thus has the potential to transform the therapeutic landscape and improve outcomes for patients with traumatic coma.